Tissue harvested from a variety of organisms has found wide spread use in the fabrication of bioprosthetic devices for implanting in both humans and animals. Most notably, prosthetic heart valves fabricated from either mature bovine pericardium or porcine heart valves are important in the management of valvular heart disease. Additionally, animal tissue implant technology has been applied with various degrees of success to other prosthetic devices such as skin, tendons, ligaments, pericardial patches, vascular tissues and collagen implants. Collagen is the most prevalent protein found in these prosthetic devices and the technology of tissue implant devices centers on the chemistry of this protein.
Typically, bioprosthetic devices prepared from harvested tissue are pretreated before the implant procedure with a protein cross-linking reagent. This chemical cross-linking treatment substantially decreases the tendency of the collagenous animal tissue to biodegrade when implanted in a recipient. The increased biostability of the tissue is attributed to a three dimensional cross-linked proteinaceous tissue network having enhanded physical and chemical stability. The cross-linking also decreases the rate of bioprosthetic immunological implant rejections which are caused by anaphylactic reactions to the foreign harvested tissue.
The most universally accepted protein cross-linking agent utilized in connection with pretreating tissue prosthetic devices is glutaraldehyde. Other aldehydes, for example formaldehyde, have also been studied for their usefulness in providing added stability to harvested tissue. However, these aldehydes are less efficient than glutaraldehyde in generating chemically, biologically, and thermally stable cross-links. In general, glutaraldehyde treated tissue exhibits viscoelastic properties which are very close to that of native collagen fibrils.
While cross-linking tissue increases the biological stability and decreases the immunological response of the bioprosthetic implant, an excessive amount of cross-linking will cause a significant loss of the natural tissue flexibility with a corresponding change in the viscoelastic properties. Highly cross-linked tissue will thus become brittle after prolonged periods of implantation and lose varying amounts of their functional advantage. Additionally, the cross-linking treatment itself has some damaging effects on the quality and the texture of the tissue implant. In particular, during the cross-linking process the tissue swells which may result in cell rupture. Tissue damage can also result from exposure to low pH solutions during various treatment steps. Another major and common problem associated with tissue bioprosthetic implants cross-linked with glutaraldehyde is the formation of calcium phosphate crystalline deposits on the altered tissue. This phenomenon, known as calcification, nearly always results in some degree of tearing and stiffening of tissue which has been treated with cross-linking agents. In connection with this problem, calcification is the most frequent cause of the clinical failure of bioprosthetic heart valves fabricated from glutaraldehyde pretreated porcine aortic valves or bovine pericardium.
While increased glutaraldehyde uptake by harvested tissue increases the tissue's biological stability, the degree of tissue calcification is enhanced. See The Role of Glutaraldehyde-Induced Cross-links in Calcification of Bovine Pericardium Used in Cardiac Valve Bioprostheses, Golomb et al , Am. J. Pathol. 127, 122-130 (1987). Also see Biochemical Differences Between Dystrophic Calcification of Crosslinked Collagen Implants and Mineralization During Bone Induction, Nimni et al., Calcif. Tissue Int. (1988) 42, 313-320. Thus, decreasing the amount of cross-linking, will decrease the degree of calcification yet provide bioprosthetic tissue with limited utility because it is not biologically stable.
One approach to the problem of maintaining a physically stable yet calcification-free tissue bioprosthetic implant device is to utilize calcification inhibitors in connection with pretreating the harvested tissue. For example, U.S. Pat. No. 4,378,224 discloses covalently binding calcification inhibitors to the animal tissue during a glutaraldehyde pretreatment procedure. The process for covalently binding calcification inhibitors to the tissue requires first cross-linking the tissue with a cross-linking reagent to physically stabilize the tissue and prevent tissue swelling. Then, a calcification inhibitor is covalently bonded to residual aldehyde groups following an aldehyde cross-linking reaction; the amount of calcification inhibitor bound to the tissue being dependent upon the availability of unreacted aldehyde functionalities. This approach results in calcification-free bioprosthetic tissue implants during the first three months of implantation. However, recent long term animal model studies indicate the this pretreatment procedure merely prolongs the period in which the tissue remains calcification-free. Because this procedure does not prevent long term calcification, bioprosthetic tissue treated in this manner will eventually calcify.
Other approaches to the problem of providing calcification-free bioprosthetic devices include administering calcification inhibitors to the recipient of the implant. For example, systemic administration of ethanehydroxydiphosphonate completely inhibits the calcification of bioprosthetic heart valve tissue. However, there are severe adverse side effects associated with this approach which include irreversible bone growth inhibition and the disruption of normal bone morphology.
Yet another approach to the use of calcium inhibitors involves providing controlled release matrices for delivering a selected calcium inhibitor locally to the site of the animal tissue implant. For example, a controlled release matrix, prepared from silicone rubber and containing a diphosphonate, has been incorporated into the sewing ring of a bioprosthetic heart valve. See Inhibition of Bioprosthetic Heart Valve Calcification by Sustained Local Delivery of Ca and Na Diphosphonate via Controlled Release Matrices, Trans Am Soc Artif Intern Organs, 1986. These controlled release devices are effective for short term control of tissue calcification, but they are not effective for long term use.
Accordingly, it is an object of the present invention to provide a method for pretreating tissue which will render the resulting bioprosthetic tissue suitable for long term use as a implant device.
It is another object of the present invention to provide a process for improving the biostability of harvested tissue in a manner which will simultaneously enhance the physical and chemical stability of the harvested tissue and prevent calcification of the tissue during long term implantation.
It is still another object of the present invention to provide a process for improving the biostability of harvested tissue in a manner which will prevent immunological reactions to the tissue during long term implantation.
It is also an object of the present invention to provide a process for improving the biostability of harvested tissue in a manner which will produce bioprosthetic implant devices having viscoelastic properties similar to native collagen fibrils.